The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.
The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.
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DOI：
10.1053/j.gastro.2009.01.002
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发表时间：
2009-05
期刊：
影响因子：
29.4
通讯作者：
Yun CC
中科院分区：
文献类型：
--
作者：
Lin S;Wang D;Iyer S;Ghaleb AM;Shim H;Yang VW;Chun J;Yun CC
慢性炎症是结肠癌（CC）的危险因素。溶血磷脂酸（LPA）是一种天然产生的磷脂，介导多种对疾病过程至关重要的作用，包括炎症和癌症。LPA受体2（LPA 2）的表达在几种类型的癌症中上调，包括卵巢癌和结肠癌，但LPA和LPA 2在CC的发展和进展中的重要性尚不清楚。在这项研究中，我们试图确定LPA和LPA 2是否在体内调节CC的进展。我们通过对ApcMin/+小鼠施用LPA来检查LPA在CC进展中的潜在作用。我们通过用氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）治疗LPA 2基因缺失（LPA 2 −/−）的小鼠，确定了LPA 2在结肠肿瘤发生中的功能丧失。我们发现LPA增加Apcmin/+小鼠的肿瘤发生率。LPA 2 −/−小鼠表现出比野生型（WT）小鼠更少的粘膜损伤和肿瘤。在LPA 2 −/−小鼠中观察到上皮细胞增殖减少和β-连环蛋白、Krüppel样因子5（KLF 5）和环氧合酶-2（考克斯-2）表达减少。与WT小鼠不同，单核细胞趋化蛋白-1（MCP-1）和巨噬细胞迁移抑制因子（MIF）的诱导在LPA 2 −/−小鼠中显著减弱，巨噬细胞浸润减少。这些结果表明LPA能够促进结肠中的肿瘤发生。LPA 2的缺乏减弱了体内导致癌症进展的几种作用，因此，目前的研究将LPA 2鉴定为CC的重要调节剂。
Chronic inflammation is a risk factor for colon cancer (CC). Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including inflammation and cancer. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA2 in the development and progression of CC is unclear. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC in vivo. We examined the potential role of LPA in CC progression by administering LPA to ApcMin/+ mice. We determined the loss of LPA2 function in tumorigenesis in the colon by treating mice with genetic deletion of LPA2 (LPA2−/−) with azoxymethane (AOM) and dextran sulfate sodium (DSS). We found that LPA increased tumor incidence in Apcmin/+ mice. LPA2−/− mice showed reduced mucosal damage and fewer tumors than wild-type (WT) mice. Reduced epithelial cell proliferation and decreases in β-catenin, Krüppel-like factor 5 (KLF5), and cyclooxygenase-2 (COX-2) expression were observed in LPA2−/− mice. Unlike WT mice, induction of monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) was significantly attenuated in LPA2−/− mice with reduced infiltration by macrophages. These results show that LPA is capable of promoting tumorigenesis in the colon. The absence of LPA2 attenuates several effects that contribute to cancer progression in vivo and, hence, the current study identifies LPA2 as an important modulator of CC.
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DOI：
10.1084/jem.190.10.1375
发表时间：
1999-11-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hudson JD;Shoaibi MA;Maestro R;Carnero A;Hannon GJ;Beach DH
通讯作者：
Beach DH
DOI：
10.1073/pnas.97.24.13384
发表时间：
2000-11-21
影响因子：
11.1
作者：
Contos, JJA;Fukushima, N;Chun, J
通讯作者：
Chun, J
DOI：
10.1084/jem.20050421
发表时间：
2005-10-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li C;Dandridge KS;Di A;Marrs KL;Harris EL;Roy K;Jackson JS;Makarova NV;Fujiwara Y;Farrar PL;Nelson DJ;Tigyi GJ;Naren AP
通讯作者：
Naren AP
影响因子：
2.2
作者：
Mori, K;Kitayama, J;Nagawa, H
通讯作者：
Nagawa, H
影响因子：
64.8
作者：
Reya, T;Clevers, H
通讯作者：
Clevers, H